In vitro models to study insulin and glucocorticoids modulation of trimethyltin (TMT)-induced neuroinflammation and neurodegeneration, and in vivo validation in db/db mice.
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| Abstract |
Brain susceptibility to a neurotoxic insult may be increased in a compromised health status, such as metabolic syndrome. Both metabolic syndrome and exposure to trimethyltin (TMT) are known to promote neurodegeneration. In combination the two factors may elicit additive or compensatory/regulatory mechanisms. Combined effects of TMT exposure (0.5-1 μM) and mimicked metabolic syndrome-through modulation of insulin and glucocorticoid (GC) levels-were investigated in three models: tridimensional rat brain cell cultures for neuron-glia effects; murine microglial cell line BV-2 for a mechanistic analysis of microglial reactivity; and db/db mice as an in vivo model of metabolic syndrome. In 3D cultures, low insulin condition significantly exacerbated TMT's effect on GABAergic neurons and promoted TMT-induced neuroinflammation, with increased expression of cytokines and of the regulator of intracellular GC activity, 11β-hydroxysteroid dehydrogenase 1 (11β-Hsd1). Microglial reactivity increased upon TMT exposure in medium combining low insulin and high GC. These results were corroborated in BV-2 microglial cells where lack of insulin exacerbated the TMT-induced increase in 11β-Hsd1 expression. Furthermore, TMT-induced microglial reactivity seems to depend on mineralocorticoid receptor activation. In diabetic BKS db mice, a discrete exacerbation of TMT neurotoxic effects on GABAergic neurons was observed, together with an increase of interleukin-6 (IL-6) and of basal 11β-Hsd1 expression as compared to controls. These results suggest only minor additive effects of the two brain insults, neurotoxicant TMT exposure and metabolic syndrome conditions, where 11β-Hsd1 appears to play a key role in the regulation of neuroinflammation and of its protective or neurodegenerative consequences.
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| Authors | Jenny Sandström, Denise V Kratschmar, Alexandra Broyer, Olivier Poirot, Philippe Marbet, Boonrat Chantong, Fanny Zufferey, Tania Dos Santos, Julien Boccard, Roman Chrast, Alex Odermatt, Florianne Monnet-Tschudi |
| Journal | Archives of toxicology (Arch Toxicol) Vol. 93 Issue 6 Pg. 1649-1664 (06 2019) ISSN: 1432-0738 [Electronic] Germany |
| PMID | 30993381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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